Clinical, Histopathologic, and Genetic Features of Patients with Myofibrillary and Distal Myopathies: Experience from the Italian Network

Neurology Medicine Respiratory System Genetics Cardiovascular System Life Sciences
Myofibrillary Myopathies Distal Myopathies Clinical Features Histopathologic Features Genetic Features Italian Network Molecular Confirmation

Clinical, Histopathological, and Genetic Characterization: Insights from Myofibrillar and Distal Myopathies Patients in the Italian Network

Background and Research Motivation

Myofibrillar Myopathies (MFM) and Distal Myopathies (DM) are a group of rare diseases with complex pathological presentations. The diagnosis process is extremely complicated due to the numerous causative genes and many molecularly undetermined disease entities and symptom overlaps. Therefore, this study aims to characterize a large cohort of patients affected by MFM and DM, identifying the most critical aspects of diagnosis and prognosis. This study was authored by Sara Bortolani et al., involving multiple Italian research institutions, and published in the Neurology® journal (2024).

Study Source

This paper was authored by Sara Bortolani, Marco Savarese, Gaetano Vattemi, and other scholars, primarily using data from multiple neuromuscular centers in Italy. The article was published in the Neurology® journal, Volume 4, 2024.

Study Design

This study is a retrospective, multicenter national study, including patients with myofibrillar myopathy or clinically diagnosed distal myopathy. Demographic, genetic, clinical, and histopathological data of anonymized patients were collected through the Italian Muscular Dystrophy Association’s neuromuscular center network.

Study Process

This study includes the following major steps: 1. Inclusion and Exclusion Criteria: - Inclusion criteria include: pathological diagnosis of MFM assessed by experienced myopathy pathologists, patients with known pathogenic gene variants, and patients with clinical presentations primarily affecting the feet and/or hands. - Exclusion criteria include: facioscapulohumeral muscular dystrophy, myotonic dystrophy, or inclusion body myositis, and patients lacking historical data.

  1. Data Collection and Analysis:
    • Demographic data: including gender, age, etc.
    • Genetic and clinical data: pathogenic genes, age of onset, and symptom characteristics.
    • Histopathological data: muscle biopsies, pathological features, enzyme activity, and electrophysiological test results.

Overview of Results

Patient Cohort

The study ultimately included 361 patients, with 132 classified as MFM patients, 298 as DM patients, and 69 classified as DM-MP (distal myopathy with myofibrillar pathology). The molecular diagnosis rate for MFM and DM was found to be 63%.

Main Pathogenic Genes: - In the MFM group, the main pathogenic genes were DES (30 cases), MYOT (20 cases), and DNAJB6 (18 cases), accounting for 83% of diagnosed patients. - In the DM group, common pathogenic genes were GNE (44 cases) and MYH7 (23 cases), accounting for 47% of diagnosed cases.

Clinical Characteristics and Functional Status

Age of Onset: - MFM patients generally showed a later age of onset (average 44.7 years), while DM patients had an earlier onset (average 34.6 years). Variants of certain genes like MYH7 and DYSF often presented before age 25, while MYOT-related patients had a later onset.

Initial Symptoms: - 30% of MFM patients initially presented with distal lower limb weakness, 29% with proximal lower limb weakness. Cardiac symptoms such as cardiomyopathy initially appeared in 5% of patients. - In DM patients, the largest proportion (65%) reported distal lower limb weakness.

Joint Contractures and Other Signs: - Joint contractures were present in 19% of MFM patients and 21% of DM patients. Scapular winging was more common. Bulbar and ocular symptoms were less common.

Histopathological Data and Auxiliary Tests

Muscle Pathology Testing: - Among 97 MFM patients, 80% of samples were from proximal muscles, and rimmed vacuoles (RVs) were detected in 55% of specimens. - Among 223 DM patients, 41% of samples were from the vastus lateralis muscle, and RVs were detected in 43% of samples.

Muscle Enzyme Levels: - Elevated creatine kinase (CK) levels were found in 56% (167 cases) of patients, with significantly elevated CK levels in distal myopathy patients related to DYSF and ANO5.

Cardiac and Respiratory Involvement

Cardiac Involvement: - Cardiac involvement was present in 29% of MFM patients and 16% of DM patients, with DES and MYH7 gene variants significantly associated with cardiomyopathy development. Structural cardiomyopathy was predominantly dilated cardiomyopathy.

Respiratory Involvement: - 25% of MFM and 12% of DM patients showed impaired respiratory function, with 30% requiring non-invasive ventilation.

Conclusion

This study systematically describes the clinical, histopathological, and genetic characteristics of MFM and DM patients in Italy, revealing significant associations between specific gene variants and cardiac and respiratory complications or loss of mobility, which are critical for the diagnosis and prognosis of these diseases. The results indicate that although there is considerable phenotypic variation, just five genes account for most molecular diagnoses, highlighting the importance of genetic screening in diagnostics. Multidisciplinary collaboration is recommended in managing these patients, especially for DES variants, to prevent severe cardiac complications.

Study Highlights

  • By systematically aggregating data from multiple healthcare institutions, this study covers the largest cohort of myofibrillar and distal myopathy patients to date.
  • Emphasizes the key role of specific gene variants in disease prognosis, aiding molecular diagnosis in clinical practice.
  • Provides detailed data on the functional status of patients at various stages, highlighting the importance of systematic follow-up.

These findings not only greatly enrich the pathological feature repository of MFM and DM but also provide important baseline data for future research.